Increasingly it has become apparent that the neuromuscular system - like other vital physiological systems - displays sexually dimorphic characteristics in structure (fiber size and fiber type composition) and function (bioenergetic pathways and resistance to fatigue). More recently, evidence has shown that men and women also experience different adaptations to muscle unloading. That is, women experience significantly greater unloading induced declines in muscle function than men. To date, the evidence suggests that the greater sensitivity of women to muscle unloading is related to more pronounced decrements in neural activation of muscle (i.e. EMG activity) and not to sex specific differences in muscle atrophy. The overall goal of this proposed project is to determine the nature and locus of sex specific declines in neural activation of muscle brought about by muscle unloading. This will be approached by comparing unloading induced diminutions in functional neuromuscular transmission efficacy, neuromuscular junction morphology, myofiber profiles (fiber type and size) and the expression of NCAM and Synaptotagmin, two important regulatory molecules of synaptic function and structure. The project's 1st Aim will focus on examining neuromuscular remodeling in response to muscle unloading in young adult males vs. females. The 2nd Aim will examine the effect of aging on sex specific adaptations to unloading;this is vital since the aged are far more likely to suffer accidental falls and medical procedures resulting in muscle unloading. In the 3rd Aim, the causative effect of sexually dimorphic sex steroid endocrine milieus on sex specific adaptations to unloading will be evaluated. In the experiments proposed here, male and female rats will be used as subjects for the project (young adults for Aim 1, aged for Aim 2, gonadectomized young adults for Aim 3), and the hind limb suspension model of unloading will be employed. The data gathered here will provide novel insight into the newly reported and clinically important finding that male and female neuromuscular systems suffer different degrees of disturbance due to muscle unloading. By understanding the nature of this sex specific remodeling, it will be possible to optimize rehabilitative strategies following the condition of muscle unloading that occurs all too frequently in men and women of all ages. PUBLIC HEALTH RELEVANCE: As a result of medical procedures and accidental falls thousands of Americans - both young and old - are subjected to muscle unloading each year eliciting impairments in neuromuscular function. Recent findings indicate that gender influences unloading induced declines in neuromuscular function. Understanding the locus and factors accounting for this gender specific remodeling is essential in order to optimize rehabilitative strategies for recovering young and aged men and women.